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Eur J Pediatr (2003) 162: 476–480
DOI 10.1007/s00431-002-1144-0
O RI G I N AL PA PER
Georgios Baroutis Æ Joseph Kaleyias
Theodora Liarou Æ Eugenia Papathoma
Zoe Hatzistamatiou Æ Christos Costalos
Comparison of three treatment regimens of natural surfactant
preparations in neonatal respiratory distress syndrome
Received: 21 May 2002 / Accepted: 26 November 2002 / Published online: 23 April 2003
Ó Springer-Verlag 2003
Abstract The aim of the study was to compare the
treatment regimen of three natural surfactants of different
extraction and formulation (Alveofact [Surfactant A =
SA], Poractant [Surfactant B = SB] and Beractant
[Surfactant C = SC]) in neonatal respiratory distress
syndrome (RDS). Premature infants of £ 32 weeks’
gestation with birth weight of £ 2,000 g and with
established RDS requiring artificial ventilation with a
FiO2 ‡0.3 were randomly assigned to receive at least two
doses of SA, SB or SC (100 mg/kg per dose). Infants who
remained dependent on artificial ventilation with a FiO2
‡0.3 received up to two additional doses. There were no
differences among the groups regarding the necessity for
more than two doses. The SA and the SB groups spent
fewer days on a ventilator (p-value SA/SB 0.7, SA/SC
0.05, SB/SC 0.043) compared with the SC group, needed
fewer days of oxygen administration (p-value SA/SB 0.14,
SA/SC 0.05, SB/SC 0.04) and spent fewer days in hospital
(p-value SA/SB 0.65, SA/SC 0.04, SB/SC 0.027). There
were no statistically significant differences in the incidence
of mortality, chronic lung disease, air leaks, necrotising
enterocolitis, retinopathy of prematurity and intraventricular haemorrhage among the three groups. Conclusion: The Alveofact and Poractant groups spent fewer
days on the ventilator, needed fewer days of oxygen
administration and spent fewer days in hospital compared with the Beractant group but no differences were
observed among the three groups with regards to mortality and morbidity.
G. Baroutis Æ J. Kaleyias (&) Æ T. Liarou Æ E. Papathoma
Z. Hatzistamatiou Æ C. Costalos
Department of Neonatal Medicine,
General District Hospital ‘‘Alexandra’’,
Athens, Greece
J. Kaleyias
31 Atho Street, 26226
Patra, Greece
E-mail: kalevias@hotmail.com
Tel.: +30-610-311981
Fax: +30-610-220511
Keywords Surfactant Æ Respiratory distress
syndrome Æ Alveofact Æ Poractant Æ Beractant
Abbreviations RDS respiratory distress syndrome Æ SA
surfactant A (Alveofact) Æ SB surfactant B
(Poractant) Æ SC surfactant C (Beractant) Æ OI
oxygenation index Æ VEI ventilatory efficiency
index Æ CLD chronic lung disease Æ PDA patent ductus
arteriosus Æ NEC necrotising enterocolitis Æ ROP
retinopathy of prematurity Æ IVH intraventricular
haemorrhage
Introduction
It is widely accepted that treatment with natural or
synthetic surfactant preparations substantially reduces
mortality as well as morbidity in infants with respiratory
distress syndrome (RDS). A wide variety of surfactant
preparations have been developed and tested. These include synthetic surfactants and surfactants derived from
animal resources [11]. Pre-clinical trials have demonstrated differences both in the in vitro and in vivo surfactants that are commercially available [6, 8, 12, 14].
Meta-analysis of 11 randomised controlled clinical
trials comparing administration of synthetic surfactants
with administration of natural surfactant extracts in
premature infants at risk of having RDS showed greater
early improvement in the requirement for ventilator
support, fewer air leaks and fewer deaths associated with
natural surfactant preparations [9]. Recently, Clark et al.
[4] compared retrospectively the outcomes of a large
series of neonates treated with two different natural
surfactants (Infusurf and Survanta) and found no
difference regarding mortality.
The present study was designed prospectively to
compare the outcome of infants with RDS treated with
three natural surfactants of different extraction and
formulation: Alveofact (bovine), Poractant (porcine)

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477
Table 1 Population characteristics. SA Alveofact, SB Poractant, SC Beractant
SA (n=27)
Birth weight (g)
Mean ± SD
Median
(25th, 75th percentile)
Gestational age (weeks)
Mean ± SD
Median
(25th, 75th percentile)
Sex ratio (male/female)
In vitro fertilization
Prenatal steroids ‡24h
Rupture of membranes
‡24h
Caesarean section
SB (n=27)
SC (n=26)
p-value* SA/SB
p-value* SA/SC
p-value* SB/SC
1,195±390
1,120
(890–1,530)
1,233±380
1,280
(920–1,550)
1,180±410
1,135
(856–1,540)
0.79
0.83
0.67
29±1.2
29
(27–30)
15/12
5/27
9/27
5/27
28.7±0.5
29
(28–30)
16/11
5/27
7/27
6/27
29.2±1
29
(28–30)
10/16
3/26
8/26
4/26
0.59
0.95
0.57
1
1
0.5
0.8
0.275
0.7
0.9
0.9
0.17
0.7
0.9
0.8
15/27
19/27
15/26
0.39
1
0.33
*Fisher’s Exact Test
and Beractant (bovine + synthetic DPPC, tripalmitin
and palmitic acid).
Materials and methods
Premature infants of £ 32 weeks’ gestation with birth weight
£ 2,000 g, born in the same perinatal centre, were enrolled in the
trial if they had RDS that had been established within the first 24 h
of life and required mechanical ventilation with a FiO2 >0.3. Informed written parental consent was required. Exclusion criteria
were major congenital or chromosomal abnormalities or anomalies
interfering with lung development or function (such as cyanotic
congenital heart disease, diaphragmatic hernias, pulmonary hypoplasia and hydrops fetalis), congenital sepsis, with blood culture
positive for pathogen within first 24 h of life, or pneumonia and
severe asphyxia.
Infants were randomly assigned using sealed envelopes to receive at least two doses (100 mg of surfactant/kg) of Alveofact
(Surfactant A = SA), Poractant (Surfactant B = SB) or Beractant
(Surfactant C = SC). The initial dose of surfactant was administered as soon as possible after intubation and stabilisation but
within 4 h of birth, while the second dose was given 12 h later.
Third and fourth doses were administered depending on the infant’s clinical situation. The method of surfactant administration
for the SA and the SB was by rapid bolus infusion directly into the
distal endotracheal tube, after disconnecting the baby from
mechanical ventilation. On the other hand, SC was given slowly by
pump via a side port adaptor to the endotracheal tube as recommended on the package insert.
Only conventional ventilation was used. The ventilator strategies
to initiate ventilation and to wean patients from the ventilator were
standardised. The typical start settings for mechanical ventilation
were: PIP 18–25 cmH2O, PEEP 4–6 cmH2O, gas flow rate 6–8 l/
min, ventilator rate 60/min, inspiratory/expiratory ratio 1:2, inspiratory time 0.33 s and expiratory time 0.67 s. The assessment of
RDS severity was based on the oxygenation index (OI = [mean
airway pressure {cmH2O}·FiO2·100]/postductal PaO2 [mmHg])
[1]. The dynamic compliance of the lungs was estimated with the
Ventilatory Efficiency Index (VEI = 3,800: [{inspiratory pressure )
end expiratory pressure} · respiratory rate · PaCO2]). The weaning
started when the infant required FiO2<0.4, was able to maintain
satisfactory blood gases at a low rate ( £ 20 breaths/min), needed
low inspiratory pressure ( £ 15 cmH2O) and was clinically and
metabolically stable.
The three groups were compared with respect to the following
NICU-related morbidities: chronic lung disease (CLD) (oxygen
dependency beyond 36 weeks’ PCA) [15], patent ductus arteriosus
(PDA) (echocardiograms and Doppler measurements to assess
shunting if clinical signs of PDA were detected), air leaks
(pneumothorax or pulmonary intestinal emphysema) [16], retinopathy of prematurity (ROP) [5], necrotising enterocolitis (NEC)
(confirmed) [2] and intraventricular haemorrhage (IVH) (‡II) [13].
Discharge criteria were weight around 2 kg, feeding well on breast
or bottle, not oxygen dependent and thermo regulating well.
Quantitative variables were compared using the Mann-Whitney
U test. For qualitative variables, the Fisher’s exact test was used.
Statistical analysis was performed using the SPSS package (SPSS
Inc., Cary, NC, USA).
Results
Population characteristics
There were no differences among the SA, SB and SC
groups regarding birth weight and gestational age
(Table 1). In addition, the three groups were similar
regarding sex ratio, in vitro fertilisation, prenatal steroids
administration, rupture of membrane and mode of
delivery.
Respiratory distress syndrome status
The severity of the RDS estimated by the FiO2, the OI
and the mean airway pressure before the administration
of the first dose of surfactant was similar among the
three groups (Table 2).
There were no significant differences among groups in
the VEI 6 h before weaning and the rate of administration of third and fourth doses of surfactant.
The SA and SB groups spent fewer days on a ventilator and needed fewer days of oxygen administration
compared with the SC group.
Correlation of the outcome with the surfactant
preparation
The mortality rates before discharge were 25.9% in
Alvofact, 18.5% in Curosurf and 23% in the Survanta
group (p=not significant; Table 3).

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Table 2 Status of respiratory distress syndrome (RDS)
p-value*SA/SB
p-value*SA/SC
p-value*SB/SC
0.58±0.13
0.54
(0.44–0.67)
0.9
0.65
0.7
0.32±0.33
0.33
(0.16–0.43)
0.34±0.22
0.28
(0.14–0.48)
0.17
0.21
0.92
8.3±2.4
9
(7.5–10)
8±1.5
8.5
(7–10)
8.5±2
8
(7–9)
0.52
0.19
0.59
1.6±0.6
0.8
(0.58–1.41)
5/27
0.9±0.3
0.75
(0.46–0.9)
4/27
1.5±0.4
0.7
(0.5–2)
6/26
Intubation days
Mean ± SD
Median
(25th, 75th percentile)
Range
6.6±2.1
4
(4–9)
1–31
5.7±1.5
4
(2–11)
1–28
11.5±2.3
5
(3–11)
2–45
Oxygen days
Mean ± SD
Median
(25th, 75th percentile)
Range
8.7±3.2
8
(5–14)
1–95
9.9±4.1
7
(4–15)
1–107
16±5.7
10
(5–20)
1–150
SA
(n=27)
SB
(n=27)
SC
(n=26)
FiO2
Mean ± SD
Median
(25th, 75th percentile)
0.65±0.15
0.55
(0.45–0.70)
0.68±0.1
0.59
(0.47–0.72)
PaO2/PAO2
Mean ± SD
Median
(25th, 75th percentile)
0.32±0.35
0.18
(0.11–0.44)
Mean airway pressure before the first dose
Mean ± SD
Median
(25th, 75th percentile)
Ventilatory Efficiency Index
<6 h before weaning
Mean ± SD
Median
(25th, 75th percentile)
Infants received >2
doses of surfactant
0.56
0.213
0.92
0.71
0.465
0.27
0.7
0.05
0.043
0.44
0.05
0.04
*Mann-Whitney U test
Table 3 Mortality and
morbidity incidence
*Fisher’s Exact Test
SA (n=27)
SB (n=27)
SC (n=26)
p-value*
SA/SB
p-value*
SA/SC
p-value*
SB/SC
7/27
3/27
5/27
2/27
4/27
2/27
5/27
5/27
4/27
4/27
3/27
5/27
3/27
6/27
6/26
4/26
5/26
4/26
3/26
2/26
4/26
0.74
0.64
1
1
1
1
1
1
0.69
1
0.41
1
1
0.5
0.74
0.69
0.72
0.69
1
1
0.72
Death before discharge
Chronic lung disease
Patent ductus arteriosus
Air leaks
Retinopathy of prematurity
Necrotizing enterocolitis
Intraventricular
hemorrhage (‡II grade)
There were no significant differences in the incidence
of CLD, PDA, air leaks, NEC, IVH and ROP among
the three groups.
The SA and SB groups spent fewer days in the
hospital compared with the SC group (p-values: SA/SB
0.65, SA/SC 0.04, SB/SC 0.027). The length of stay at
the hospital for infants with no CLD was similar for all
three groups (Table 4).
Discussion
There are many clinical comparisons between synthetic
and natural surfactants and they all conclude that treat-
ment with natural surfactant resulted in a greater reduction in the severity of RDS [9, 10, 19, 20], but at the time of
the study design there were very few studies comparing
natural surfactants [3, 4, 17]. Bloom et al. [3] compared
two natural surfactants (Infasurf and Survanta) and
concluded that infants treated with Infasurf had a modest
benefit in the acute phase of RDS, but there were no
significant differences in the incidence of air leaks, complications associating with dosing, complications of prematurity, mortality or survival without chronic lung
disease. Recently, Clark et al. [4] compared the same
surfactants (Infasurf/Survanta) and concluded that the
most important variables associated with neonatal death,
IVH or NEC were birth weight and gestational age, while

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Table 4 Length of stay at
hospital and body weight at
discharge
SA
SB
SC
Hospital days
Number assessed
Mean ± SD
Median
Range
20
62±20
49
30–149
22
48±15
47
28–135
20
81±28
55
23–165
Hospital days (no CLD)
Number assessed
Mean ± SD
Median
Range
19
57±16
58
30–80
21
45 ±17
46
28–82
17
63±24
54
23–126
Body weight at discharge (g)
Number assessed
20
22
20
Mean ± SD
2,130±60
2,100±97
2,120±60
Median
2,130
2,090
2,100
Range
2,030–2,250 2,000–2,280 2,010–2,200
*Mann-Whitney U test
Corrected postmenstrual
age at discharge (weeks)
Number assessed
Mean ± SD
Median
Range
the type of surfactant did not significantly influence the
outcome. Speer et al. [17] compared Beractant and Poractant and they concluded that Beractant treatment resulted in a more rapid improvement in oxygenation than
Poractant and reduced ventilatory requirements up to
24 h after the start of treatment. In addition, they found a
trend towards reduced incidence of serious pulmonary
and non-pulmonary complications in the Beractant
group.
We found that the Alveofact and the Poractant
groups spent fewer days on mechanical ventilation and
needed fewer oxygen administration days. The Beractant
group spent more days in hospital, but this difference did
not exist when infants with CLD were excluded from the
analysis. There were no statistical differences among
these three groups with regards to the major NICU related morbidities. Obviously, the numbers of infants are
too small to show definite results. As previously noted,
Clark et al. [4] studied a large series of neonates and
concluded that previously reported differences did not
exist.
Differences in the composition of Beractant and
Alveofact or Poractant may account for different clinical
efficacy observed. Beractant contains phospholipids
from lung cells as well as lung surfactant. It has higher
levels of non-phosphatidylcholine phospholipids such
as sphingomyelins and phosphatidylethanolamines and
these phospholipids limit the lowest surface tension
attainable in bovine surfactant preparations [7]. There is
a step in the Beractant process that removes cholesterol,
but it also removes the surfactant apoprotein B, the
apoprotein most critical for full biophysical activity [12,
20]. Another reason, which is possibly responsible for
differences observed in clinical activity, is the method of
surfactant administration. We administered Beractant
20
36.9±1.7
37
35–42
22
36.4±1.5
36
34–40
22
38±3.6
37
36–46
479
p-value* p-value* p-value*
SA/SB
SA/SC
SB/SC
0.65
0.04
0.027
0.19
0.75
0.28
0.12
0.42
0.43
0.25
0.27
0.036
by pump via a side port in the endotracheal tube adaptor
by pump according to the manufacturer’s recommendation. As other researchers have shown, there is an
uneven distribution of surfactant when it is given as a
slow infusion, leading to a poor clinical response [20].
Obviously, a serious bias regarding the methods was
that the study was not blinded with regard to the
administration of surfactant. The study was blinded
with regards to Poractant and Alveofact but blinding
was not possible in the case of Beractant due to the
different method of administration.
In conclusion, in the present study we have observed:
1. Reduced intubation and oxygen days for infants who
received Poractant and Alveofact compared with
Beractant
2. Fewer days spent in hospital for babies treated with
Poractant and Alveofact compared with Beractant
3. No statistical differences among the three studied
surfactants with regards to mortality and the major
NICU-related morbidities
However, the numbers of patients in the present
study were small in each group and more trials are
needed before any firm conclusions can be drawn
regarding the choice of the most efficacious natural
surfactant.
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